Biological and lifestyle factors contributing to Tau in women at risk for Alzheimer's disease.

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PROJECT SUMMARY/ABSTRACT Growing evidence reports that women show a more aggressive profile of Alzheimer's disease (AD) than men with greater pathological tau burden and steeper cognitive decline; yet the reasons for these sex differences are poorly understood. Sex differences in AD point to sex-disparate causal pathways as well as sex-specific therapeutic targets. Neuroinflammation (N-Inf) is one candidate casual pathway that shows sex disparities and plays a central role in AD pathogenesis with close ties to both tau and cognitive decline. Women tend to have a more robust immune/inflammatory response and comprise 80% of autoimmune disease cases. Moreover, our own preliminary work in the Alzheimer's Disease Neuroimaging Initiative indicated that women may be more susceptible than men to the adverse effect of N-Inf, particularly the markers of TNFα, IL6 and their receptors on cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and cognitive function. There are also lifestyle factors such as physical activity and obstructive sleep apnea (OSA) known to influence N- Inf and relate to tau and cognitive decline and to do so differently in women versus men. Our own preliminary data highlight sedentary behavior and obstructive sleep apnea as two modifiable risk factors that show strong associations with N-Inf, tau and/or cognitive function in older women, and thus stress the need to further understand how and to what degree these lifestyle interventions could reduce AD risk. Together, these findings led us to this proposed observational study that will examine how N-Inf markers (specifically TNFα, TNFR2, IL6 and IL6R) and the modifiable risk factors that influence N-Inf relate to tau accumulation and cognitive decline in older women at-risk for AD by way of mild cognitive deficits and genetic risk. Moreover, we will explore how sex hormones, particularly testosterone, contribute to these relationships given their anti-inflammatory and central nervous system effects and often contributing role to sex differences. To achieve this, we propose to measure CSF N-Inf markers, physical activity, OSA, and circulating sex hormones in a sample of 100 older women at-risk for AD and relate these measures to changes in cognitive function and accumulation of tau, measured via positron emission tomography (PET), over a two-year period. This study will build upon a state-funded, pilot study by increasing the sample size and adding longitudinal assessments in order to conduct a rigorous examination of our hypotheses. In keeping with NIH research priorities, after 5 years of potential funding, this project will help to close critical gaps in our understanding of sex differences in AD by examining under-explored yet highly-relevant mechanisms that may contribute to the greater pathology and steeper cognitive decline in women on the AD trajectory. Furthermore, our findings will inform risk reduction strategies that influence these mechanisms – an important focus given current the lack of disease-modifying treatments.